Multi-Omic Analysis Reveals Lipid Dysregulation Associated with Mitochondrial Dysfunction in Parkinson's Disease Brain

Abstract

Parkinsons Disease (PD) is an increasingly prevalent condition within the aging population. PD can be attributed to rare genetic mutations, but most cases are sporadic where the gene-environment interactions are unknown/likely contributory. Age related dysregulation of the glycosphingolipid degradation pathway has been implicated in the development of PD, however, our understanding of how brain lipids vary across different regions of the brain, with age and in disease stages, remains limited. In this study we profiled several phospho- and sphingolipid classes in eight distinct regions of the human brain and investigated the association of lipids with a spatio-temporal pathology gradient, utilising PD samples from early, mid, and late stages of the disease. We performed high-precision tissue sampling in conjunction with targeted LC-MS/MS and applied this to post-mortem samples from PD and control subjects. The lipids were analysed for correlations with untargeted proteomics and mitochondrial activity data, in a multi-omics approach. We concluded that the different brain regions demonstrated their own distinct profiles and also found that several lipids were correlated with age. The strongest differences between PD and controls were identified in ganglioside, sphingomyelin and n-hexosylceramides. Sphingomyelin was also found to correlate with several proteins implicated in Parkinsons disease pathways. Mitochondrial activity was correlated with the levels of several lipids in the putamen region. Finally, we identified a gradient corresponding to Braaks disease spread across the brain regions, where the areas closer to the brainstem/substantia nigra showed alterations in PC, LPC and glycosphingolipids, while the cortical regions showed changes in glycosphingolipids, specifically gangliosides, HexCer and Hex2Cer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/604051v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@d4851eorg.highwire.dtl.DTLVardef@6f9d00org.highwire.dtl.DTLVardef@1ac9d7dorg.highwire.dtl.DTLVardef@197808e_HPS_FORMAT_FIGEXP M_FIG C_FIG